This invention relates to the use of certain indole and indazole derivatives in the treatment of migraine. Further, the invention relates to certain N-alkylamino indole and indazole compounds, to pharmaceutical and diagnostic compositions containing them and to their medical use, particularly in the treatment or diagnosis of CNS conditions.
Through its interaction with receptors found on neuronal and other cells, 5-hydroxytryptamine (5-HT or serotonin) mediates a variety of physiological effects. Imbalances in this interaction are believed to be responsible for such conditions as anxiety, hallucination, migraine, chemotherapy-induced nausea and for disorders in sexual activity, cardiovascular activity and thermoregulation, amongst others. From an improved understanding of the 5-HT receptor population it is apparent that these effects are mediated selectively through individual types and subtypes of the 5-HT receptors. Migraine, for example, has been treated with ergotamine, dihydroergotamine, methylsergide and, most recently, sumatriptan, all of which presumably act at the 5-HT1D receptor subtype.
Current treatments for migraine, including sumatriptan, continue to have unwanted side effects. These include coronary vasospasm, hypertension and angina. Recent evidence suggests that the observed sumatriptan-mediated contraction of coronary arteries may be due to the stimulation of the 5-HT1B (formerly 5-HT1Dxcex2) subtype of the 5-HT receptors (Kaumann, A. J. Circulation, 1994, 90:1141-1153).
Given the physiological and clinical significance of the 5-HT1D receptor, and the potential side effect liability of stimulation of the 5-HT1B receptor, it would be desirable to provide compounds that bind with high affinity to the 5-HT1D receptor. Such compounds would be medically useful, for example, to treat indications for which administration of a 5-HT1D ligand is indicated, such as migraine. Such compounds could also be used diagnostically, for example, to identify these receptors and to screen drug candidates.
It has been found that compounds of Formula I, 
wherein:
X is selected from the group consisting of N, CH and C-lower alkyl;
R1 represents a 5 to 7-membered monocyclic or benzo-fused heterocyclic ring, which may be unsaturated, and which may contain one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino and mono- or di-lower alkyl amino;
Ak represents a C1-3alkylene chain which may be substituted with R2, where R2 represents lower alkyl;
R3 and R4 are independently selected from the group consisting of H, lower alkyl, lower alkenyl, cycloalkyl and optionally-substituted benzyl; or one pair of R2 and
R3 or R3 and R4 together may form an alkylene or alkenylene bridge which, with the nitrogen atom, form a 3- to 7-membered ring which may contain one or more substituents selected from the group consisting of lower alkyl, hydroxy, hydroxymethyl, alkoxymethyl, amino and substituted amino;
R5 is selected from the group consisting of H, lower alkyl and a 4- to 7-membered carbocyclic or heterocyclic group, which may be unsaturated
and salts and solvates thereof, bind to the Serotonin 5-HT1D receptor and are, therefore, useful, in accordance with one aspect of the invention, for the treatment of diseases such as migraine.
In another aspect of the invention, compounds of Formula I, and radio-labeled forms thereof, are also useful as a pharmacological tool for the identification of other compounds, including potential drug candidates, which bind to the 5-HT1D receptor.
Radio-labeled forms of compounds of Formula I are also useful as diagnostic tools for the identification of 5-HT1D binding sites in vitro.
According to another aspect of the present invention there are provided compounds of Formula II and a salt, solvate or hydrate thereof: 
wherein:
X is selected from the group consisting of N, CH and C-lower alkyl;
R6 represents a 5 to 7-membered monocyclic or benzo-fused heterocyclic ring, which may be unsaturated, and which may contain one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino and mono- or di-lower alkyl amino;
Ak represents a C1-3alkylene chain which may be substituted with R7, where R7 represents lower alkyl;
R8 and R9 are independently selected from the group consisting of H, lower alkyl, lower alkenyl, cycloalkyl and optionally-substituted benzyl;
R10 is selected from the group consisting of H, lower alkyl and a 4- to 7-membered carbocyclic or heterocyclic group, which may be unsaturated.
It is another aspect of the present invention to provide compounds which bind selectively to the 5-HT1D receptor, relative particularly to the 5-HT1B receptor.
According to another aspect of the invention there are provided compositions comprising a compound of Formula I and a carrier, either for use as reagents, for example in the identification of 5-HT1D receptors or 5-HT1D receptor ligands, or for pharmaceutical use to treat conditions where stimulation of the 5-HT1D receptor is indicated.
According to another aspect of the invention there are provided compositions comprising a compound of Formula II and a carrier.
It is another aspect of the present invention to provide a method effective to treat medical conditions for which stimulation of the 5-HT1D receptor is indicated, such as migraine.
These and other aspects of the present invention are described in greater detail hereinbelow.
The term xe2x80x9clower alkylxe2x80x9d as used herein means straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein means a 3- to 7-membered carbocyclic ring and includes cyclopropyl, cyclohexyl and the like.
The term xe2x80x9clower alkoxyxe2x80x9d as used herein means straight and branched chain alkoxy radicals containing from one to six carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
The term xe2x80x9coptionally substituted benzylxe2x80x9d as used herein means an unsubstituted benzyl radical or a benzyl radical substituted on the phenyl ring with 1-3 substituents independently selected from halo, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, CF3 and CF3O.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d means an acid addition salt which is compatible with the treatment of patients.
A xe2x80x9cpharmaceutically acceptable acid addition saltxe2x80x9d is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of their intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluenesulfonic and methanesulfonic acids. Either the mono- or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts e.g. oxalates may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
The term xe2x80x9csolvatexe2x80x9d means a compound of Formula I, or a pharmaceutically acceptable salt of a compound of Formula I, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate.
The term xe2x80x9cstereoisomersxe2x80x9d is a general term for all isomers of a molecule which differ only in the orientation of their atoms in space. It includes image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre which are not mirror images of one another (diastereomers).
The term xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d means an amount of the compound which is effective in treating the named disorder or condition.
The term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.
The present invention includes within its scope prodrugs of the compounds of Formula I. In general, such prodrugs will be functional derivatives of a compound of Formula I which are readily convertible in vivo into the compound from which it is notionally derived. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d ed. H. Bundgaard, Elsevier, 1985.
Compounds of Formula I bind to the serotonin 5-HT1D receptor. Preferred compounds of Formula I bind selectively (for example with 10-fold selectivity) to the serotonin 5-HT1D receptor, relative, particularly, to the serotonin 5-HT1B receptor, as judged by in vitro binding affinities using, for example, the assay exemplified herein. More preferred compounds are those which bind with at least 10-fold selectivity to the 5-HT1D receptor, relative to the 5-HT1B receptor. Most preferred are those compounds which bind with at least 40-fold selectivity to the 5-HT1D receptor, relative to the 5-HT1B receptor.
Some of the compounds of Formula II may have at least one asymmetric centre. Where the compounds according to the invention have one asymmetric centre they may exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
Acid addition salts of the compounds of Formula II are most suitably formed with pharmaceutically acceptable acids, and include, for example, those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid. Other non-pharmaceutically acceptable salts e.g. oxalates may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
The conversion of a given compound salt to a desired compound salt is achieved by standard techniques in which an aqueous solution of the given salt is treated with a solution of base e.g. sodium carbonate, potassium hydroxide to liberate the neutral compound which is then extracted into an appropriate solvent, such as ether. The neutral compound is then separated from the aqueous portion, dried, and treated with the requisite acid to give the desired salt.
Also included within the scope of the invention are solvates of the compounds of the invention. The formation of a solvate will vary depending on the compound and solvent used. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.
Prodrugs of compounds of the invention may be conventional esters formed with available hydroxyl (or thiol) or carboxyl groups. For example, when one of R3 or R4 in a compound of Formula I contains an OH group, it may be acylated using an activated acid in the presence of a base and, optionally, in inert solvent (e.g. an acid chloride in pyridine). Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.
Compounds of Formula I include those in which R1 is a monocyclic or benzo-fused heterocyclic ring. Preferably, R1 is a monocyclic ring (such as pyridinyl or thienyl). More preferably R1 is a non-aromatic ring (such as piperidinyl, pyranyl or thiopyranyl), and may contain a hydroxy substituent. Most preferably, the ring is unsubstituted. In general, heterocyclic rings containing O or S are preferred over N-containing rings.
The alkylene chain Ak is preferably unsubstituted, and is, more preferably, a 2-carbon chain.
R3 and R4 are, preferably, independently selected small groups such as methyl, ethyl, cyclopropyl and the like. More preferably, R3 and R4 are methyl, most preferably one of R3 or R4 is methyl and the other is H.
R5 is, preferably, H or lower alkyl, more preferably H or Me and, most preferably, R5 is H.
The novel compounds of Formula II, which form another aspect of the invention, follow, broadly, the SAR outlined above for the compounds of Formula I (that is, the preferred compounds follow the same trend).
Specific compounds useful in the treatment of migraine include:
(R)-1-((N-Methylpyrrolidin-2-yl)methyl)-6-(3-pyridinyl)-1H-indole;
(R)-1-((N-Methylpyrrolidin-2-yl)methyl)-6-(3-thienyl)-1H-indole;
(R)-1-(2-(N-(2-Hydroxymethyl)pyrrolidinyl)ethyl)-6-(3-thienyl)-1H-indazole;
(R)-1-(N-Methylpyrrolidin-2-yl)methyl)-6-(1-methyl-1,2,5,6-tetrahydro-4-pyridine)-1H-indole;
(R)-1-(N-Methylpyrrolidin-2-yl)methyl)-6-(3-thienyl)-1H-indazole;
(R)-1-(Pyrrolidin-2-yl)methyl)-6-(3-thienyl)-1H-indazole;
(R)-6-(4-Hydroxy-N-methylpiperidin-4-yl)-1-(N-methylpyrrolidin-2-yl)methyl)-1H-indole;
(R)-6-(N-Methylpiperidin-4-yl)-1-(N-methylpyrrolidin-2-yl)methyl)-1H-indole;
(R,S)-1-(2-(N,N-Dimethylamino)propyl)-6-(1-methyl-1,2,5,6-tetrahydro-4-pyridine)-1H-indole;
(R,S)-1-(2-(N,N-Dimethylamino)propyl)-6-(3-pyridinyl)-1H-indole;
(R,S)-1-(2-(N,N-Dimethylamino)propyl)-6-(3-thienyl)-1H-indole;
(S)-1-((N-Methylpyrrolidin-2-yl)methyl)-6-(3-pyridinyl)1H-indole;
(S)-1-((N-Methylpyrrolidin-2-yl)methyl)-6-(2-thienyl-1H-indole;
(S)-1-(2-(N-(2-Hydroxymethyl)pyrrolidinyl)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(1-Azetidinyl)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-(1-Benzylpyrrolidin-3-yl)amino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-(3-Hydroxypyrrolidinyl)ethyl))-6-(3-thienyl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(1-tert-butoxycarbonyl-pyrrol-2-yl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(2,3-dihydrothiopyran-4-yl)-1H-indole;
1-(2-(N,N-Diethylamino)ethyl)-6-(3-pyridinyl)-1H-indole;
1-(2-(N,N-Diethylamino)ethyl)-6-(3-thiophene)-1H-indole;
1-(2-(N,N-Diethylamino)ethyl)-6-(4-hudroxy-tetrahydrothiopyran-4-yl)-1H-indole;
1-(2-(N,N-Diethylamino)ethyl)-6-(4-methyl-2-thienyl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(5-chloro2-thienyl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(5-methyl-2-thienyl)-1H-indazole;
6-(Benzo[b]thien-2-yl)-1-(2-(N,N-diethylamino)ethyl)-1H-indazole;
6-(Benzo[b]furan-2-yl)-1-(2-(N,N-diethylamino)ethyl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(furan-3-yl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(N-methyltetrahydro-4-pyridinyl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(3-pyridinyl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(tetrahydropyran-4-yl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(tetrahydrothiopyran-4-yl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(tetrahydrothiopyran-4-yl)-1H-indole;
1-(2-(N,N-Diethylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(1-methyl-1,2,5,6-tetrahydro-4-pyridine)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(4-hydroxy-tetrahydrothiopyran-4-yl)-1H-indole;
6-(6H-2,3-Dihydrothiopyran-4-yl)1-(2-(N,N-dimethylamino)ethyl)-1H-indole;
6-(Benzo[b]thiophene-2-yl)-1-(2-(N,N-dimethylamino)ethyl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(N-methyl-2,3-dihydro-4-piperidinyl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(N-methyl-4-hydroxy-4-piperidinyl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(N-methylpiperidin-4-yl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(N-methyl-piperidin-4-yl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(pyridin-2-yl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(3-pyridinyl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(3-pyridinyl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(4-pyridinyl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(tetrahydropyran-4-yl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(tetrahydrothiopyran-4-yl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(2-thienyl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(2-thienyl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)6-(3-thienyl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(3-thienyl)-1H-indole;
1-(2-(N,N-Dipropylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Allylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Benzylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Cyclopropylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Cyclopropylmethylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Isopropylamino)ethyl)-6-(3-thienyl)-1H-indazole,
1-(2-(N-Methylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Piperidinyl)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Propylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Pyrrolidinyl)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Pyrrolin-3-yl)ethyl)-6-(3-thienyl)-1H-indazole;
6-(2,3-Dihydropyran-4-yl)-1-(2-(pyrrolidinyl)ethyl-1H-indole;
6-(4-Hydroxy-tetrahydropyran-4-yl)-1-(2-(pyrrolidinyl)ethyl-1H-indole;
1-(2-(Pyrrolidinyl)ethyl-6-(tetrahydropyran-4-yl)-1H-indole;
6-(3-Pyridinyl)-1-(2-pyrrolidinyl)ethyl-1H-indole;
1-(3-(N,N-Diethylamino)propyl)-6-(3-thienyl)-1H-indazole;
1-(3-(N,N-Dimethylamino)propyl)-6-(3-pyridinyl)-1H-indole;
1-(3-(N,N-Dimethylamino)propyl)-6-(4-hydroxy-tetrahydrothiopyran-4-yl)-1H-indole;
6-(6H-2,3-Dihydrothiopyran-4-yl)-1-(3-(N,N-dimethylamino)propyl)-1H-indole;
1-(3-(N,N-Dimethylamino)propyl)-6-(tetrahydrothiopyran-4-yl)-1H-indole;
1-(3-(N,N-Dimethylamino)propyl)-6-(3-thienyl-1H-indazole;
1-(3-(N-Pyrrolin-3-yl)propyl)-6-(3-thienyl)-1H-indazole;
1-(3-N,N-Dimethylamino)propyl-6-(2-thiophene)-1H-indole
1-(N-Cyclopropylamino)ethyl)-6-(4-hydroxy-tetrahydrothiopyran-4-yl)-1H-indole;
1-(N-Cyclopropylamino)ethyl-6-(2,3-dihydrothiopyran-4-yl)-1H-indole;
1-(N-Methyl-azepan-3-yl)-6-(3-thienyl)-1H-indole;
1-(N-Methyl piperidin-2-yl)methyl)-6-(3-thienyl)-1H-indole;
3-(1-Cyclohexenyl)-1-(2-(N,N-dimethylamino)ethyl)-6-(3-Pyridyl)-1H-indole;
3-(1-Cyclohexyl)-1-(2-(N,N-dimethylamino)ethyl)-6-(3-Pyridyl)-1H-indole;
6-(3-Aminopyrrolidin-1-yl)-1-((N,N-dimethylamino)ethyl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(4-hydroxy-tetrahydropyran-4-yl)-1H-indole;
6-(6H-2,3-Dihydropyran-4-yl)-1-(2-(N,N-dimethylamino)ethyl)-1H-indole;
1-((N,N-Dimethylamino)ethyl)-6-(N-morpholinyl)-1H-indazole;
1-((N,N-Dimethylamino)ethyl)-6-(N-morpholinyl)-1H-indole;
1-((N,N-Dimethylamino)ethyl)-6-(N-thiomorpholinyl)-1H-indole and
1-(2-(N,N-Dimethylamino)ethyl)-6-(tetrahydropyran-4-yl)-1H-indole.
Preferred embodiments of the invention include:
(R)-1-((N-Methylpyrrolidin-2-yl)methyl)-6-(3-pyridinyl)-1H-indole;
(R)-1-((N-Methylpyrrolidin-2-yl)methyl)-6-(3-thienyl)-1H-indole;
(R)-1-(2-(N-(2-Hydroxymethyl)pyrrolidinyl)ethyl)-6-(3-thienyl)-1H-indazole;
(R)-1-(N-Methylpyrrolidin-2-yl)methyl)-6-(3-thienyl)-1H-indazole;
(R)-1-(Pyrrolidin-2-yl)methyl)-6-(3-thienyl)-1H-indazole;
(R,S)-1-(2-(N,N-Dimethylamino)propyl)-6-(3-pyridinyl)-1H-indole;
(R,S)-1-(2-(N,N-Dimethylamino)propyl)-6-(3-thienyl)-1H-indole;
(S)-1-((N-Methylpyrrolidin-2-yl)methyl)-6-(2-thienyl)-1H-indole;
(S)-1-((N-Methylpyrrolidin-2-yl)methyl)-6-(3-pyridinyl) 1H-indole;
(S)-1-(2-(N-(2-Hydroxymethyl)pyrrolidinyl)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(1-Azetidinyl)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-(1-Benzylpyrrolidin-3-yl)amino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-(3-Hydroxypyrrolidinyl)ethyl))-6-(3-thienyl)-1H-indazole;
1-(2-(N-(3-tert-Butoxycarbonylamino)pyrrolidinyl)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(3-furanyl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(3-pyridinyl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(3-pyridinyl)-1H-indole;
1-(2-(N,N-Diethylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(3-thienyl)-1H-indole;
1-(2-(N,N-Diethylamino)ethyl)-6-(4-methyl-2-thienyl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(5-methyl-2-thienyl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(2-pyridinyl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(2-thienyl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(2-thienyl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(3-pyridinyl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(3-pyridinyl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(3-thienyl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(4-pyridinyl)-1H-indazole;
1-(2-(N,N-Dipropylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Allylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Benzylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Cyclopropylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Cyclopropylmethylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Isopropylamino)ethyl)-6-(3-thienyl-1H-indazole,
1-(2-(N-Methylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Piperidinyl)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Propylamino)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Pyrrolidinyl)ethyl)-6-(3-thienyl)-1H-indazole;
1-(2-(N-Pyrrolin-3-yl)ethyl)-6-(3-thienyl)-1H-indazole;
1-(3-(N,N-Diethylamino)propyl)-6-(3-thienyl)-1H-indazole;
1-(3-(N,N-Dimethylamino)propyl)-6-(3-pyridinyl)-1H-indole;
1-(3-(N,N-Dimethylamino)propyl)-6-(3-thienyl)-1H-indazole;
1-(3-(N-Pyrrolin-3-yl)propyl)-6-(3-thienyl)-1H-indazole;
1-(3-N,N-Dimethylamino)propyl-6-(2-thienyl)-1H-indole
1-(N-Methyl-3-azepinyl)-6-(3-thienyl)-1H-indole;
1-(N-Methylpiperidin-2-yl)methyl)-6-(3-thienyl)-1H-indole;
3-(1-Cyclohexenyl)-1-(2-(N,N-dimethylamino)ethyl)-6-(3-pyridyl)-1H-indole;
3-(1-Cyclohexyl)-1-(2-(N,N-dimethylamino)ethyl)-6-(3-pyridyl)-1H-indole;
6-(3-Pyridinyl)-1-(2-pyrrolidinyl)ethyl-H-indole;
6-(5-Chloro-2-thienyl)-1-(2-(N,N-diethylamino)ethyl)-1H-indazole; and
6-(Benzo[b]-2-thienyl)-1-(2-(N,N-diethylamino)ethyl)-1H-indazole.
More preferred embodiments of the invention include:
(R)-1-(N-Methylpyrrolidin-2-yl)methyl)-6-(1-methyl-1,2,5,6-tetrahydro-4-pyridinyl)-1H-indole;
(R)-6-(4-Hydroxy-N-methyl-4-piperidinyl)-1-(N-methyl-2-pyrrolidinyl)methyl)-1H-indole;
(R)-6-(N-Methyl-4-piperidinyl)-1-(N-methyl-2-pyrrolidinyl)methyl)-1H-indole;
(R,S)-1-(2-(N,N-Dimethylamino)propyl)-6-(1-methyl-1,2,5,6-tetrahydro-4-pyridinyl)-1H-indole;
1-((N-Cyclopropylamino)ethyl)-6-(2,3-dihydrothiopyran-4-yl)-1H-indole;
1-(2-(N,N-Diethylamino)ethyl)-6-(2,3-dihydrothiopyran-4-yl)-1H-indole;
1-(2-(N,N-Diethylamino)ethyl)-6-(4-hydroxy-tetrahydrothiopyran-4-yl)-1H-indole;
1-(2-(N,N-Diethylamino)ethyl)-6-(N-methyltetrahydro-4-pyridinyl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(tetrahydropyran-4-yl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(tetrahydrothiopyran-4-yl)-1H-indazole;
1-(2-(N,N-Diethylamino)ethyl)-6-(tetrahydrothiopyran-4-yl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(1-methyl-1,2,5,6-tetrahydro-4-pyridinyl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(4-hydroxy-tetrahydropyran-4-yl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(4-hydroxy-tetrahydrothiopyran-4-yl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(N-methyl-2,3-dihydro-4-piperidinyl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(N-methyl-4-hydroxy-4-piperidinyl-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(N-methyl-4-piperidinyl)-1H-indazole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(N-methyl-4-piperidinyl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(tetrahydropyran-4-yl)-1H-indazole
1-(2-(N,N-Dimethylamino)ethyl)-6-(tetrahydropyran-4-yl)-1H-indole;
1-(2-(N,N-Dimethylamino)ethyl)-6-(tetrahydrothiopyran-4-yl)-1H-indole;
1-(2-(Pyrrolidinyl)ethyl)-6-(tetrahydropyran-4-yl)-1H-indole;
1-(N-Cyclopropylamino)ethyl)-6-(4-hydroxy-tetrahydrothiopyran-4-yl)-1H-indole;
6-(2,3-Dihydropyran-4-yl)-1-((2-pyrrolidinyl)ethyl)-1H-indole;
6-(3-Amino-1-pyrrolidinyl)-1-((N,N-dimethylamino)ethyl)-1H-indole;
6-(4-Hydroxy-tetrahydropyran-4-yl)-1-(2-(pyrrolidinyl)ethyl)-1H-indole;
6-(6H-2,3-Dihydropyran-4-yl)-1-(2-(N,N-dimethylamino)ethyl)-1H-indole; and
6-(6H-2,3-Dihydrothiopyran-4-yl)-1-(2-(N,N-dimethylamino)ethyl)-1H-indole.
In accordance with another aspect of the invention, the compounds of the invention can be prepared by processes analogous to those established in the art.
For example, compounds of Formula I where R1 is a non-aromatic group can be prepared as shown below in Scheme 1. 
Intermediate A, wherein LG is a group which undergoes lithium exchange (such as halo, preferably bromo or iodo), when treated with an alkyllithium such as n- or t-butyllithium, followed by the addition of a cyclic ketone of Formula B to provide compounds of Formula C. This reaction is performed in inert solvents, such as ether or tetrahydrofuran, at temperatures ranging from xe2x88x92100 to 0xc2x0 C. Preferred conditions are tetrahydrofuran at xe2x88x9278xc2x0 C. Compounds of Formula C may be dehydrated under standard conditions, for example, by formation of the mesylate and elimination under basic conditions or, alternatively, in the presence of an acid such as trifluoroacetic acid in an inert solvent such as tetrahydrofuran, to provide compounds of Formula D. Compounds of formula D can be reduced, for example by treatment with hydrogen in the presence of a catalyst, such as palladium on charcoal, to give saturated compounds E.
Compounds of Formula I can also be prepared by direct treatment of intermediate A with the appropriate boronic acid (or ester or diester of boronic acid, as shown in scheme 2) under basic conditions, in the presence of a catalyst such as tetrakis(triphenylphosphine) palladium (0). The 6-substituent can also be introduced by treatment of intermediate A with R1SnBu3 (for example) in THF, again in the presence of a catalytic amount of tetrakis(triphenylphosphine) palladium (0). 
Alternatively, such compounds may be prepared according to Scheme 3, wherein intermediate A is converted to trialkyl tin derivative G upon treatment with a tin reagent such as hexamethylditin or hexabutyiditin in the presence of a catalyst such as tetrakis(triphenylphosphine) palladium (0). Treatment of intermediate G with, for example, a derivative of the desired R1 group containing an appropriate group (LG) gives product H. 
6-Heterocyclic substituents can be introduced as shown in scheme 3a, below, by the treatment of intermediate A with an organozinc intermediate in the presence of a nickel catalyst to give product Fxe2x80x2, or with a cyclic amine in the presence of a palladium catalyst to give product Fxe2x80x3. 
Substituents at the 3-position of the indole ring may be introduced as shown in Scheme 4. 
3-substituents can also be introduced as shown in Scheme 5. Intermediate L can then be elaborated at the 1-position using standard chemistry, for example that shown in Schemes 7 and 8. 
Alternatively, the 1-substituent can be introduced before formation of the indazole ring, as shown in scheme 6. 
For compounds where X represents N and the 1-substituent is a 2-aminoethyl derivative, the route outlined in Scheme 7 was used. 
The substituent on the indole nitrogen can be introduced in a number of ways, some of which are outlined in Scheme 8. The 6-substituent can then be introduced as shown in the preceding schemes.
For example, a 2-aminoethyl substituent can be introduced by treatment of the 1-mesylate derived from indole V with an appropriate alkoxide. The 3-carbon homologue in both the indole and indazole series can be introduced by treatment of the 1-H compound X with 1-chloro-3-iodopropane, followed by treatment of the resulting chloro compound with an appropriate amine. Compounds in which R2 is an alkyl group can be prepared, for example, by treatment of 1-H compound X with a substituted epoxide, followed by treatment of the resulting alcohol Z with an appropriate amine.
Compounds in which one of R3 or R4 and R2 form a ring (compounds BB and CC in Scheme 8) can be prepared by treatment of the 1-H compound with an appropriate amino alcohol. Interestingly, the reaction with 2-Hydroxymethyl-N-methyl-piperidine gives rise to two products, one of which is a product of ring expansion. 
It should be appreciated that one skilled in the art would realize that the sequence of reactions described above can be varied. For example, in Scheme 4, above, the group at the indole 3-position may be incorporated into the molecule before the addition of the group at the indole 6-position.
In some cases, the chemistries outlined above may have to be modified, for instance by use of protecting groups, to prevent side reactions due to reactive groups, such as reactive groups attached as substituents. This may be achieved be means of conventional protecting groups, as described in Protective Groups in Organic Chemistry, ed. McOmie, J. F. W. Plenum Press, 1973; and Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.
In another embodiment of the invention, the present compounds can be used to distinguish 5-HT1D receptors from other receptor subtypes, for example glutamate or opioid receptors, within a population of receptors, and in particular to distinguish between the 5-HT1D and other 5-HT receptor subtypes. The latter can be achieved by incubating preparations of the 5-HT1D receptor and one of the other 5-HT receptor subtypes (for example 5-HT1B) with a 5-HT1D-selective compound of the invention and then incubating the resulting preparation with a radiolabeled serotonin receptor ligand, for example [3H]-serotonin. The 5-HT1D receptors are then distinguished by determining the difference in membrane-bound activity, with the 5-HT1D receptor exhibiting lesser radioactivity, i.e., lesser [3H]-serotonin binding, than the other 5-HT receptor subtype.
In another aspect of the invention, a compound of the invention is provided in labeled form, such as radiolabeled form, e.g. labeled by incorporation within its structure 3H or 14C or by conjugation to 125I. In another aspect of the invention, the compounds in labeled form can be used as competitive ligands to identify 5-HT1D receptor ligands by techniques common in the art. This can be achieved by incubating the receptor or tissue in the presence of a ligand candidate and then incubating the resulting preparation with an equimolar amount of radiolabeled compound of the invention. 5-HT1D receptor ligands are thus revealed as those that are not significantly displaced by the radiolabeled compound of the present invention. Alternatively, 5-HT1D receptor ligand candidates may be identified by first incubating a radiolabeled form of a compound of the invention, then incubating the resulting preparation in the presence of the candidate ligand. A more potent 5-HT1D receptor ligand will, at equimolar concentration, displace the radiolabeled compound of the invention.
A radiolabeled compound of Formula I may be prepared using standard methods known in the art. For example, tritium may be incorporated into a compound of Formula I using standard techniques, for example by hydrogenation of a suitable precursor to a compound of Formula I using tritium gas and a catalyst. Alternatively, a compound of Formula I containing radioactive iodo may be prepared from the corresponding trialkyltin (suitably trimethyltin) derivative using standard iodination conditions, such as [125I] sodium iodide in the presence of chloramine-T in a suitable solvent, such as dimethylformamide. The trialkyltin compound may be prepared from the corresponding non-radioactive halo, suitably iodo, compound using standard palladium-catalyzed stannylation conditions, for example hexamethylditin in the presence of tetrakis(triphenylphosphine) palladium (0) in an inert solvent, such as dioxane, and at elevated temperatures, suitably 50-100xc2x0 C.
The present compounds are useful as pharmaceuticals for the treatment of various conditions in which the use of a 5-HT1D ligand is indicated, such as for the treatment of migraine, cluster headache and portal tension, a condition characterized by increased portal vein blood flow and typically associated with cirrhosis of the liver.
For use in medicine, the compounds of the present invention can be administered in a standard pharmaceutical composition. The present invention therefore provides, in a further aspect, pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof, in an amount effective to stimulate the 5-HT1D receptor.
The compounds of the present invention may be administered by any convenient route, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration. Appropriate pharmaceutical compositions will be formulated accordingly.
Compounds of Formula I and their stereoisomers, solvates, hydrates or pharmaceutically acceptable salts for oral administration can be formulated as liquids, for example syrups, suspensions, solutions or emulsions, or as solid forms such as tablets, capsules and lozenges, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. A liquid formulation will generally consist of a suspension or solution of the compound (or pharmaceutically acceptable salt thereof) in a suitable pharmaceutical liquid carrier such as ethanol, glycerine, polyethylene glycol, oils, or water with a suspending agent (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats), preservative (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid), flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsule. Alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier, for example aqueous gums, celluloses, silicates or oils, and the dispersion or suspension filled into a soft gelatin capsule.
Compounds of the present invention may be formulated for parenteral administration by injection, including using conventional catheterisation techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules, or in multi-dose containers, with an added preservative. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form, in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer. Capsules and cartridges of, for example, gelatin for use in an inhaler or atomizing device may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are prepared in the form of, for example, suppositories or retention enemas, and may contain a conventional suppository base such as cocoa butter or other glycerides.
A proposed dose of the compounds of the invention for oral, buccal, sublingual or rectal administration to a human (of about 70 kg body weight) for the treatment of migraine is 0.1 mg to 500 mg, for example 0.5 mg to 100 mg, preferably 1 mg to 50 mg, of active ingredient per dose, administered up to 8 times per day, more usually 1 to 4 times per day. It will be appreciated that it may be necessary to make routine changes to the dosage depending on the age and weight of the patent as well as the severity of the condition to be treated. It should be understood that unless otherwise indicated, the dosages are referred to in terms of the weight of the compound of Formula I calculated as the free base.
The overall daily dosage administered by injection may be in the range of 0.1 mg to 100 mg, preferably between 0.1 mg and 50 mg, e.g., between 1 mg and 25 mg, of a compound of Formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof calculated as the free base, the compound being administered 1 to 4 doses per day.
Aerosol formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d delivered from a pressurized aerosol contains 0.1 to 10 mg of a compound of the invention, and each dose administered via capsules and cartridges in an inhaler contains 0.1 to 50 mg of a compound of the invention. Administration may be several times daily, for example 2 to 8 times, giving for example 1,2 or 3 doses each time. The overall daily dose by inhalation will be similar to that for oral administration.
The compounds of the invention may, if desired, be administered in combination with one or more other therapeutic agents, such as analgesics, anti-inflammatory agents and anti-nauseants.